Evaluation of Muc1 Gene Expression at The Time of Implantation in Diabetic Rat Models Treated with Insulin, Metformin and Pioglitazone in The Normal Cycle and Ovulation Induction Cycle

Background Mucin-1(Muc1) is one of the first molecules in the endometrium that confronts implanting embryos. There is insufficient knowledge about the impacts of diabetes and drugs developed for diabetes treatment on expres- sion of this molecule at the time of implantation. Therefore, this study aimed to investigate the impacts of diabetes and insulin, metformin and pioglitazone on Muc1 expression at the time of implantation. Materials and Methods This experimental study was conducted on a total of 63 female Wistar rats divided into 9 groups. To induce type 1diabetes, streptozotocin (STZ) and for induction of type 2 diabetes, nicotinamide (NA) and STZ were injected intraperitoneally. For superovulation, human menopausal gonadotropin (HMG) and human chori- onic gonadotropin (HCG) were used. Insulin, metformin and pioglitazone were administered for two weeks. Finally, the endometrial expression of Muc1 was evaluated by quantitative real-time reverse transcription–polymerase chain reaction (RT-PCR). Results Muc1 expression was non-significantly increased in type 1 and type 2 diabetic groups compared to the con- trol group (P=0.61 and 0.13, respectively); also, it increased in insulin-treated type 1 diabetic group compared to the control group (P=0.0001). Its expression was increased in insulin-treated type 1 diabetic group compared to untreated diabetic group (P=0.001). The expression level of Muc1 was significantly reduced in superovulated and insulin-treated type 1 diabetic group compared to the insulin-treated type 1 diabetic group (P=0.001). Conclusion One of the causes of fertility problems in diabetes, is changes in Muc1 expression during implantation. On the other hand, the use of insulin in these patients can even lead to overexpression of this gene and worsen the condition. However, these changes can be partially mitigated by assisted reproductive technology (ART) such as su- perovulation. Also, treatment with metformin and pioglitazone can restore Muc1 expression to near normal levels and has beneficial effects on implantation.

[1]  P. Nikpour,et al.  Evaluation of Diabetes Effects on the Expression of Leukemia Inhibitory Factor and Vascular Endothelial Growth Factor A Genes and Proteins at the Time of Endometrial Receptivity after Superovulation in Rat Model , 2019, Advanced biomedical research.

[2]  Chi-Chiu Wang,et al.  Decreased MUC1 in endometrium is an independent receptivity marker in recurrent implantation failure during implantation window , 2018, Reproductive Biology and Endocrinology.

[3]  B. Roelen,et al.  Exposure to elevated glucose concentrations alters the metabolomic profile of bovine blastocysts , 2018, PloS one.

[4]  Bingshu E. Chen,et al.  CA15-3/MUC1 in CCTG MA-32 (NCT01101438): A phase III RCT of the effect of metformin vs. placebo on invasive disease free and overall survival in early stage breast cancer (BC). , 2018 .

[5]  Jhohann Richard de Lima Benzi,et al.  The role of organic cation transporter 2 inhibitor cimetidine, experimental diabetes mellitus and metformin on gabapentin pharmacokinetics in rats , 2018, Life sciences.

[6]  Xihui Sheng,et al.  Expression and function of MUC1 in uterine tissues during early pregnancy in sheep after natural oestrous or artificially-induced oestrous. , 2018, Theriogenology.

[7]  Frank B. Hu,et al.  Global aetiology and epidemiology of type 2 diabetes mellitus and its complications , 2018, Nature Reviews Endocrinology.

[8]  H. Pattison,et al.  Type 2 diabetes in adolescents and young adults. , 2018, The lancet. Diabetes & endocrinology.

[9]  P. Tang,et al.  Superovulation at a specific stage of the estrous cycle determines the reproductive performance in mice. , 2016, Reproductive biology.

[10]  L. Eissa,et al.  Modulating effects of omega-3 fatty acids and pioglitazone combination on insulin resistance through toll-like receptor 4 in type 2 diabetes mellitus , 2016 .

[11]  B. Campbell,et al.  In vivo and in vitro studies of MUC1 regulation in sheep endometrium. , 2016, Theriogenology.

[12]  R. Jha,et al.  Endoglin (CD105) coordinates the process of endometrial receptivity for embryo implantation , 2016, Molecular and Cellular Endocrinology.

[13]  C. Forsblom,et al.  Age at menarche and the risk of diabetic microvascular complications in patients with type 1 diabetes , 2016, Diabetologia.

[14]  E. Baştu,et al.  Role of Mucin 1 and Glycodelin A in recurrent implantation failure. , 2015, Fertility and sterility.

[15]  A. Ghasemi,et al.  Streptozotocin-nicotinamide-induced rat model of type 2 diabetes (review). , 2014, Acta physiologica Hungarica.

[16]  H. Chan,et al.  Ion channels in the endometrium: regulation of endometrial receptivity and embryo implantation. , 2014, Human reproduction update.

[17]  J. Kastelic,et al.  Mucin 1 and cytokines mRNA in endometrium of dairy cows with postpartum uterine disease or repeat breeding. , 2014, Theriogenology.

[18]  B. Stoica,et al.  Protective effect of magnesium and metformin on endometrium and ovary in experimental diabetes mellitus. , 2014, Magnesium research.

[19]  P. Hompes,et al.  Pregnancy complications and metabolic disease in women with clomiphene citrate-resistant anovulation randomized to receive laparoscopic electrocautery of the ovaries or ovulation induction with gonadotropins: a 10-year follow-up. , 2014, Fertility and sterility.

[20]  A. Uysal,et al.  Evaluation of the Effects of STZ-Induced Diabetes on In Vitro Fertilization and Early Embryogenesis Processes , 2013, Journal of diabetes research.

[21]  F. Kan,et al.  Endometrial Receptivity Defects and Impaired Implantation in Diabetic NOD Mice1 , 2012, Biology of reproduction.

[22]  L. Roshangar,et al.  Progesterone and ovarian stimulation control endometrial pinopode expression before implantation in mice. , 2012, Pathophysiology : the official journal of the International Society for Pathophysiology.

[23]  J. Tuomilehto,et al.  Fertility in people with childhood-onset type 1 diabetes , 2012, Diabetologia.

[24]  S. Kimber,et al.  Early stages of implantation as revealed by an in vitro model. , 2010, Reproduction.

[25]  U. Eriksson,et al.  Altered uterine perfusion is involved in fetal outcome of diabetic rats. , 2008, Placenta.

[26]  E. Jungheim,et al.  The impact of type 1 and type 2 diabetes mellitus on the oocyte and the preimplantation embryo. , 2008, Seminars in reproductive medicine.

[27]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[28]  W. Cefalu,et al.  Efficacy of inhaled human insulin in type 1 diabetes mellitus: a randomised proof-of-concept study , 2001, The Lancet.

[29]  E. Seregni,et al.  Hormonal Regulation of MUC1 Expression , 1999, The International journal of biological markers.